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Despite the SARS-CoV-2 onset of mass vaccination campaigns, the pandemic exhibits unprecedented extent of morbidity and mortality. Consequently, there is still an urgent need for effective therapeutics. The virus spike (S) glycoprotein, essential for the recognition of its human cognate angiotensin-converting enzyme 2 (hACE2) receptor on target cells and subsequent viral internalization, was implicated as the main target for coronavirus-neutralizing monoclonal antibodies (mAbs). Processing of the S protein by host proteases results in the generation of the S1 subunit, responsible for receptor engagement, and the S2 subunit, which mediates membrane fusion. Two functional domains can be distinguished within the S1 subunit: the N-terminal domain (NTD) and the C-terminal domain (CTD). The NTD of SARS-CoV-2 is important for SARS-CoV-2 infectivity.
The spike NTD may represents an important element involved in SARS-CoV-2 infectivity, and therefore, a possible additional target for neutralizing antibodies. The recent emergence of escape variants further encouraged consideration of neutralizing mAbs against NTD as a therapeutic strategy, possibly in combination with anti-RBD
mAbs.